Most cancer therapeutics require continuous dosing to overcome the logarithmic re-growth of tumors. In contrast, T cells targeted to cancer via tumor associated antigens (TAA), can expand for an initial clinical effect and, then to be self-sustained and effective over long intervals due to the acquisition of immunological memory. Ample experimental data in mice support these concepts and there is substantial clinical evidence that certain cancers, in particular melanoma, undergo sustained remissions when T cell mediated immunity against TAAs is activated by cancer vaccines, cell-based therapies or monoclonal antibodies (1,4,5). However, the low frequency of such responses and the limited spectrum of tumor types that show objective responses to immunotherapy have been disappointing. Tumors evolve mechanisms that resist immunotherapy by blocking cell death pathways, by suppressina the expression of target antigens or by generating immunosuppressive microenvironments. Recent data(6,7) suggest that, in some patients, these resistance mechanisms can be circumvented by combining ACT with TCR gene therapy. This novel approach dramatically increases the number of CTLs that express effective anti-tumor TCRs. We and others hypothesize that this approach will dramatically enhance the efficacy of the ACT therapy for melanoma patients, and for other major cancers.